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Comparison of vaccination with rhesus CMV (RhCMV) soluble gB with a RhCMV replication-defective virus deleted for MHC class I immune evasion genes in a RhCMV challenge model

Valencia, Sarah, Gill, Rachel B., Dowdell, Kennichi C., Wang, Yanmei, Hornung, Ron, Bowman, J. Jason, Lacayo, Juan C., Cohen, Jeffrey I.
Vaccine 2019 v.37 no.2 pp. 333-342
CD8-positive T-lymphocytes, Human herpesvirus 5, Macaca mulatta, alum, cell-mediated immunity, epithelial cells, fibroblasts, glycoproteins, immune evasion, kidneys, lipid A, major histocompatibility complex, models, monkeys, neutralizing antibodies, saliva, urine, vaccination, vaccines, viral shedding, viruses
A human cytomegalovirus (HCMV) vaccine to prevent infection and/or reduce disease associated with congenital infection or visceral disease in transplant recipients is a high priority, but has remained elusive. We created a disabled infectious single cycle rhesus CMV (RhCMV) deleted for glycoprotein L (gL) and the MHC class I immune evasion genes Rh178 and Rh182-189, and restored its epithelial cell tropism by inserting the Rh128-131A genes. The resulting virus, RhCMVRΔgL/178/182–189, was used to vaccinate rhesus monkeys intramuscularly and was compared with vaccination of animals with soluble RhCMV glycoprotein B (gB) in alum/monophosphoryl lipid A or with PBS as a control. At 4 weeks after the second vaccination, an increased frequency of RhCMV-specific CD8 T cells was detected in animals vaccinated with the RhCMVRΔgL/178/182–189 vaccine compared to animals vaccinated with soluble gB. In contrast, monkeys vaccinated with soluble gB had 20-fold higher gB antibody titers than animals vaccinated with RhCMVRΔgL/178/182–189. Titers of neutralizing antibody to RhCMV infection of fibroblasts were higher in animals vaccinated with gB compared with RhCMVRΔgL/178/182–189. Following vaccination, monkeys were challenged subcutaneously with RhCMV UCD59, a low passage virus propagated in monkey kidney epithelial cells. All animals became infected after challenge; however, the frequency of RhCMV detection in the blood was reduced in monkeys vaccinated with soluble gB compared with those vaccinated with RhCMVRΔgL/178/182–189. The frequency of challenge virus shedding in the urine and saliva and the RhCMV copy number shed at these sites was not different in animals vaccinated with RhCMVRΔgL/178/182–189 or soluble gB compared with those that received PBS before challenge. Although the RhCMVRΔgL/178/182–189 vaccine was superior in inducing cellular immunity to RhCMV, it induced lower titers of neutralizing antibody and antibody to gB than the soluble gB vaccine; after challenge, animals vaccinated with soluble gB had a lower frequency of virus detection in the blood than those vaccinated with RhCMVRΔgL/178/182–189.